Physiochemical Properties

Question 1

What must an “ideal” oral drug be?

Answer 1

Dissolve
Survive in 1.5-8.0 pH range
Survive intestinal bacteria
Cross membranes
Survive liver metabolism
Avoid active transport to bile
Avoid excretion by kidneys
Partition into target organ
Avoid partition to undesired places

Question 2

What is a physiochemical property?

Answer 2

A parameter that can be derived from physical + chemical characteristics of a molecule

Question 3

What are the physiochemical properties?

Answer 3

Solubility
Stability
Solid-state properties
Partition coefficient
Ionisation constant

Question 4

What is Lipinski’s rule of 5?

Answer 4

No more than 5 H bonds
No more than 10 H bond donors
Mr <500
LogP <5

Question 5

What is lipophilicity?

Answer 5

Ability of chemical compound to dissolve in fats, oils, lipids + non-polar solvents

Question 6

What does lipophilicity determine?

Answer 6

ADMET

Question 7

What does it mean if logP is high?

Answer 7

High lipophilicity

Question 8

How do you determine logP using shake flask method?

Answer 8

Look at distribution between octanol + H2O
Analyse drug conc by UV

Question 9

How do you determine logP using chromatography?

Answer 9

Microtiter plate format
Compound detection by MS
Retention time linked to partition coefficient
Limited by compound properties - eg. purity

Question 10

What is clogP?

Answer 10

Calculated logP

Question 11

What happens to binding as logP increases?

Answer 11

Increases

Question 12

What happens to aqueous solubility as logP increases?

Answer 12

Decreases

Question 13

What happens to absorption through membrane as logP increases?

Answer 13

Increases

Question 14

What is the substituent hydrophobicity constant?

Answer 14

Measure of substituent’s hydrophobicity relative to H

Question 15

What does positive values of the substituent hydrophobicity constant indicate?

Answer 15

More hydrophobic (lipophilic) than H

Question 16

What does negative values of the substituent hydrophobicity constant indicate?

Answer 16

Less hydrophobic than H

Question 17

How is it possible to calculate logP (clogP) from substituent hydrophobicity constant?

Answer 17

LogP + value + value

Question 18

What do you use when comparing neutral molecules?

Answer 18

logP

Question 19

What do you use when comparing mixed neutral + charged molecules?

Answer 19

logP

Question 20

What do you use when comparing all charged molecules?

Answer 20

logD

Question 21

What happens to logD in acidic drugs when pKa increases?

Answer 21

More ionised = logD decreases

Question 22

What happens to logD in basic drugs when pKa increases?

Answer 22

LogD increases

Question 23

Describe fluorine

Answer 23

Small atom
High electronegativity

Question 24

What does covalently bound fluorine do?

Answer 24

Occupy vol smaller than methyl, amino or hydroxyl groups
BUT larger than H atom

Question 25

When you add F to an acid what happens? CH3COOH ----> CH2FCOOH

Answer 25

pKa decreases = increased acidity

Question 26

What happens to lipophilicity if you substitute H for F?

Answer 26

Increases lipophilicity slightly

Question 27

What happens to logD if you substitute H for F?

Answer 27

Decreases

Question 28

What are the ways of investigating molecular size?

Answer 28

e- density Molecular weight Polar surface area Van der Waals Molar refractivity

Question 29

What is the Hammett substituent constant?

Answer 29

A measure of electron-withdrawing or electron-donating influence of substituents

Question 30

How can the Hammett substituent constant be measured?

Answer 30

Experimentally or tabulated

Question 31

What will electron-withdrawing groups have? Hammett substituent constant

Answer 31

Positive value

Question 32

What will electron-donating groups have? Hammett substituent constant

Answer 32

Negative value

Question 33

What happens in electron-withdrawing groups? Hammett substituent constant

Answer 33

Charge stabilised by X Eqm shifts right Kx > KH

Question 34

What happens in electron-donating groups? Hammett substituent constant

Answer 34

Charge destabilised Eqm shifts left Kx < KH

Question 35

What are the 2 types of substitution?

Answer 35

Meta Para

Question 36

What is meta due to?

Answer 36

Inductive effect

Question 37

What is para due to?

Answer 37

Inductive + resonance effects

Question 38

Describe aliphatic electronic effects

Answer 38

Purely inductive effects Hydrolysis rates measured under basic + acidic conditions Defined by σI

Question 39

If X is electron donating what will happen to hydrolysis rate of aliphatic electronic effects?

Answer 39

Decreases

Question 40

If X is electron withdrawing what will happen to hydrolysis rate of aliphatic electronic effects?

Answer 40

Increases

Question 41

What is molecular polar SA?

Answer 41

Surface sum of all polar atoms present in the molecule Usually N, O + their attached H

Question 42

How is molecular polar SA calculated?

Answer 42

From surface/space filling models

Question 43

How do rotatable bonds effect?

Answer 43

Increased flexibility reduces oral bioavailability = <10

Question 44

How do H bond donors + acceptors effect?

Answer 44

Polarity reduces permeability Lipinski's rule

Question 45

How do aromatic rings effect?

Answer 45

Effect solubility

Question 46

How does pKa effect?

Answer 46

Drug needs to be ionised pKa needs to be relevant to logD + target binding site

Question 47

What does it mean if there is a high logS value?

Answer 47

Good solubility